The present invention relates to compounds that are useful for treating inflammatory diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation in a mammal.
Inflammation results from a cascade of events that includes vasodilation accompanied by increased vascular permeability and exudation of fluid and plasma proteins. This disruption of vascular integrity precedes or coincides with an infiltration of inflammatory cells. Inflammatory mediators generated at the site of the initial lesion serve to recruit inflammatory cells to the site of injury. These mediators (chemokines such as IL-8, MCP-1, MIP-1, and RANTES, complement fragments and lipid mediators) have chemotactic activity for leukocytes and attract the inflammatory cells to the inflamed lesion. These chemotactic mediators which cause circulating leukocytes to localize at the site of inflammation require the cells to cross the vascular endothelium at a precise location. This leukocyte recruitment is accomplished by a process called cell adhesion.
Cell adhesion occurs through a coordinately regulated series of steps that allow the leukocytes to first adhere to a specific region of the vascular endothelium and then cross the endothelial barrier to migrate to the inflamed tissue (Springer, T. A., 1994, Traffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigm, Cell 76: 301-314; Lawrence, M. B., and Springer, T. A., 1991, Leukocytes"" Roll on a Selectin at Physiologic Flow Rates: Distinction from and Prerequisite for Adhesion Through Integrins, Cell.65: 859-873; von Adrian, U., Chambers, J. D., McEnvoy, L. M., Bargatze, R. F., Arfos, K. E, and Butcher, E. C., 1991, Two-Step Model of Leukocyte-Endothelial Cell Interactions in Inflammation, Proc. Natl. Acad. Sci. USA 88: 7538-7542; and Ley, K., Gaehtgens, P., Fennie, C., Singer, M. S., Lasky, L. H. and Rosen, S. D., 1991, Lectin-Like Cell Adhesion Molecule 1 Mediates Rolling in Mesenteric Venules in vivo, Blood 77: 2553-2555). These steps are mediated by families of adhesion molecules such as integrin, Ig supergene family members, and selectins which are expressed on the surface of the circulating leukocytes and on the vascular endothelial cells. The first step consists of leukocyte rolling along the vascular endothelial cell lining in the region of inflammation. The rolling step is mediated by an interaction between leukocyte surface oligosaccharides (such as Sialylated Lewis-X antigen (Slex)) and a selectin molecule expressed on the surface of the endothelial cell in the region of inflammation. The selectin molecule is not normally expressed on the surface of endothelial cells but rather is induced by the action of inflammatory mediators such as TNF-xcex1 and interleukin-1. Rolling decreases the velocity of the circulating leukocyte in the region of inflammation and allows the cells to more firmly adhere to the endothelial cell. The firm adhesion is accomplished by the interaction of integrin molecules that are present on the surface of the rolling leukocytes and their counter-receptors-the Ig superfamily molecule-on the surface of the endothelial cell. The Ig superfamily molecules or CAMs (Cell Adhesion Molecules) are either not expressed or are expressed at low levels on normal vascular endothelial cells. The CAM""s, like the selecting, are induced by the action of inflammatory mediators like TNF-alpha and IL-1. The final event in the adhesion process is the extravasation of the leukocyte through the endothelial cell barrier and the migration of the leukocyte along the chemotactic gradient to the site of inflammation. This transmigration is mediated by the conversion of the leukocyte integrin from a low avidity state to a high avidity state. The adhesion process relies on the induced expression of selectins and CAM""s on the surface of vascular endothelial cells to mediate the rolling and firm adhesion of leukocytes to the vascular endothelium.
The induced expression of e-selectin and CAM""s is mediated by the transcription factor NFkB. NFKB is a family of dimeric transcription factors made from monomers containing the 300 amino acid Rel domain. These factors can bind to DNA, interact with each other and bind to an inhibitor molecule termed IkB (Vermaa, I. M., Stevenson, J. K., Schwarz, E. M., Antwerp, D. V., and Miyamoto, S, 1995, Rel/NFlB/IkB Family: Intimate Tales of Association and Dissociation, Genes Dev. 9: 2723-2735; and Baldwin, A. S. 1996, The NFkB and IkB proteins: New Discoveries and Insights, Annu. Rev. Immunol. 14: 649-681). NFkB is found in the cytoplasm complexed with IkB. Activation of NFKB occurs in response to inflammatory mediators such as TNF-xcex1, IL-1, and lipopolysaccharide. Activation of IkB requires phosphorylation of IkB followed by ubiquitinylation of the IkB molecule and subsequent degradation by proteosomes. Release of NFkB from association with IkB results in translocation of the dimer to the nucleus where it can associate with specific DNA sequences. The e-selectin gene and CAM""s contain NFkB-recognition sequences upstream from their coding regions. The DNA-bound NFKB acting with other proteins in the transcription complex directs the expression of the e-selectin and CAM genes among others controlled by this transcription factor.
The present invention discloses compounds that inhibit the expression of e-selectin and ICAM-1 relative to VCAM-1. These compounds are useful for the treatment or prophylaxis of diseases caused by expression of adhesion molecules. These diseases include those in which leukocyte trafficking plays a role, notably acute and chronic inflammatory diseases, autoimmune diseases, tumor metastasis, allograft rejection, and reperfusion injury.
In one embodiment of the present invention are disclosed compounds represented by structural Formula I: 
or a pharmaceutically acceptable salt or prodrug thereof, where the symbol  represents a single bond or a double bond, provided that when one bond is a double bond, the adjacent bond is a single bond;
E, F, and G are independently selected from
(1) carbon,
(2) nitrogen, and
(3) N+xe2x80x94Oxe2x88x92,
provided that at least one of E, F or G is nitrogen or N+xe2x80x94Oxe2x88x92, and further provided that at least one of E, F or G is carbon;
Y and Z are independently selected from
(1) carbon,
(2) nitrogen,
(3) oxygen, and
(4) S(O)t where t is an integer 0-2,
provided that at least one of Y or Z is other than carbon;
LA is selected from
(1) a covalent bond,
(2) xe2x80x94Oxe2x80x94,
(3) xe2x80x94S(O)txe2x80x94,
(4) xe2x80x94NR6xe2x80x94 where R6 is selected from
(a) hydrogen,
(b) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from,
(i) aryl and
(ii) cycloalkyl of three to ten carbons,
(c) alkanoyl where the alkyl part is of one to ten carbons, and
(d) cycloalkyl of three to ten carbons,
(5) xe2x80x94C(W)xe2x80x94 where W is selected from
(a) O and
(b) S, and
(6) alkenylene;
XA is selected from
(1) halo,
(2) alkyl of one to ten carbons optionally substituted with 1, 2, or 3 substituents independently selected from
(a) oxo,
(b) cycloalkyl of three to ten carbons,
(c) xe2x80x94CO2R7 where R7 is selected from
(i) hydrogen and
(ii) alkyl of one to ten carbons optionally substituted with 1, or 2 substituents independently selected from
aryl and
cycloalkyl of three to ten carbons,
(d) xe2x80x94NR8R9 where R8 and R9 are independently selected from
(i) hydrogen,
(ii) alkyl of one to six carbons optionally substituted with 1 or 2 substituents independently selected from
xe2x80x94OH,
aryl,
heterocycle,
cycloalkyl of three to ten carbons, and
xe2x80x94NRARB where RA and RB are independently selected from
hydrogen and
alkyl of one to six carbons optionally substituted with 1 or 2 substituents selected from xe2x80x94OH,
(iii) alkanoyl where the alkyl part is of one to to ten carbons,
(iv) cycloalkyl of three to ten carbons,
(v) alkoxy,
(vi) heterocycle, and
(vii) aryl,
xe2x80x83where (vi) and (vii) are substituted with 1 or 2 substituents independently selected from
alkyl of one to six carbons and
halo,
(e) xe2x80x94C(W)R10 where W is previously defined and R10 is selected from
(i) hydrogen,
(ii) alkyl of one to ten carbons optionally substituted with 1, or 2 substituents independently selected from
aryl and
cycloalkyl of three to ten carbons,
(iii) xe2x80x94NR8R9, and
(iv) xe2x80x94OR7,
(f) xe2x80x94OH,
(g) aryl, and
(h) heterocycle,
where (g) and (h) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(i) alkyl of one to twenty carbons,
(ii) xe2x80x94NR8R9,
(iii) alkoxy of one to ten carbons,
(iv) thioalkoxy of one to ten carbons,
(v) halo,
(vi) perfluoroalkyl of one to three carbons,
(vii) alkenyl of two to ten carbons,
(viii) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
alkoxy of one to ten carbons and
xe2x80x94OH,
(ix) xe2x80x94CO2R7,
(x) aryl, and
(xi) xe2x80x94CHO,
(3) cycloalkyl of three to ten carbons,
(4) aryl,
(5) heterocycle
where (4) and (5) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) alkyl of one to twenty carbons,
(b) alkyl of one to ten carbons substituted with 1, 2, or 3 substituents independently selected from
(i) xe2x80x94OR11 where R11 is selected from
hydrogen,
xe2x80x94C(W)R12 where R12 is selected from
alkyl of one to ten carbons,
cycloalkyl of three to ten carbons,
aryl, and
heterocycle, and
heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from
xe2x80x94OH and
alkyl of one to six carbons optionally substituted with 1 or 2 substituents selected from xe2x80x94OH,
(ii) alkoxy of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
alkoxy and
alkoxyalkoxy,
(iii) spiroalkyl of three to ten carbons, and
(iv) halo,
(c) alkoxy of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
(i) alkoxy, and
(ii) alkoxyalkoxy,
(d) thioalkoxy of one to ten carbons,
(e) halo,
(f) perfluoroalkyl of one to three carbons,
(g) alkenyl of two to ten carbons optionally substituted with 1 or 2 substituents independently selected from
(i) xe2x80x94C(W)R10 and
(ii) xe2x80x94C(W)R12,
(h) xe2x80x94CO2R7,
(i) xe2x80x94NR8R9,
(j) aryl,
(k) xe2x80x94C(W)R12,
(l) xe2x80x94CHO,
(m) xe2x80x94C(O)NR8R9,
(n) xe2x80x94CN,
(o) heterocycle optionally substituted with 1 or 2 substituents independently selected from
(i) alkyl of one to ten carbons and
(ii) perfluoroalkyl of one to three carbons,
(p) xe2x80x94C(W)R10,
(q) ethylenedioxy, and
(r) xe2x80x94OCF3,
(6) xe2x80x94OR7,
(7) hydrogen, and
(8) xe2x80x94NR8R9;
LB is selected from
(1) a covalent bond,
(2) xe2x80x94Oxe2x80x94,
(3) xe2x80x94S(O)txe2x80x94,
(4) xe2x80x94NR6xe2x80x94,
(5) xe2x80x94C(W)xe2x80x94, and
(6) xe2x80x94C(xe2x95x90NR13)xe2x80x94 where R13 is selected from
(a) hydrogen,
(b) xe2x80x94NO2,
(c) xe2x80x94CN, and
(d) xe2x80x94OR14 where R14 is selected from
(i) hydrogen,
(ii) aryl, and
(iii) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents independently selected from
aryl and
xe2x80x94C(O)R15 where R15 is selected from hydrogen,
xe2x80x94OH,
alkoxy, and
NRARB;
XB is selected from
(1) hydrogen,
(2) alkyl of one to ten carbons optionally substituted with 1, 2, or 3 substituents independently selected from
(a) xe2x80x94CO2R7,
(b) xe2x80x94NR8R9,
(c) xe2x80x94C(W)NR8R9,
(d) heterocycle,
(e) aryl optionally substituted with 1 or 2 substituents independently selected from
(i) alkyl of one to ten carbons,
(ii) xe2x80x94NO2, and
(iii) xe2x80x94NRARB,
(f) xe2x80x94OR16 where R16 is selected from
(i) hydrogen and
(ii) xe2x80x94C(W)NRARB, and
(g) xe2x80x94NRAC(W)NR8R9,
(3) alkenyl of two to six carbons optionally substituted with 1 or 2 substituents independently selected from
(a) xe2x80x94C(W)NRARB,
(b) xe2x80x94CO2R7, and
(c) heterocycle,
(4) xe2x80x94NR17R18 where R17 and R18 are independently selected from
(a) hydrogen,
(b) alkyl of one to ten carbons optionally substituted with 1, 2, or 3 substituents independently selected from
(i) xe2x80x94OH,
(ii) xe2x80x94C(W)R10,
(iii) xe2x80x94NRAC(xe2x95x90NR13)NRBR19 where RA, RB, and R13 are previously defined and R19 is selected from
hydrogen,
alkyl of one to ten carbons, and
xe2x80x94NO2,
(iv) heterocycle,
(v) aryl,
(vi) halo, and
(vii) xe2x80x94NRARB,
(c) alkoxy,
(d) aryl optionally substituted with 1, 2, or 3 substituents independently selected from
(i) halo,
(ii) alkyl of one to ten carbons,
(iii) alkoxy of one to ten carbons, and
(iv) perfluoroalkyl of one to three carbons,
(e) heterocycle,
(f) xe2x80x94NRARB,
(g) xe2x80x94C(O)R20 where R20 is selected from
(i) hydrogen,
(ii) alkyl of one to ten carbons,
(iii) xe2x80x94OR12, and
(iv) xe2x80x94NRARB,
(h) cycloalkyl of three to ten carbons, and
(i) xe2x80x94OH,
(5) alkoxy,
(6) xe2x80x94OH,
(7) xe2x80x94NRAC(xe2x95x90NR13)NRBR19,
(8) xe2x80x94C(W)NR8R9,
(9) aryl,
(10) heterocycle,
where (9) and (10) can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from
(a) halo,
(b) alkyl of one to ten carbons optionally substituted with 1, 2, or 3 substituents independently selected from
(i) halo,
(ii) alkoxy of one to ten carbons,
(iii) xe2x80x94NRARB,
(iv) xe2x80x94OH,
(v) xe2x80x94CO2R7,
(vi) xe2x80x94C(W)NRARB, and
(vii) aryl,
(c) xe2x80x94NRARB,
(d) alkoxy of one to ten carbons,
(e) thioalkoxy of one to ten carbons,
(f) perfluoroalkyl of one to three carbons,
(g) xe2x80x94OH,
(h) xe2x80x94C(W)NR8R9,
(i) xe2x80x94CO2R7,
(j) xe2x80x94NRAC(W)OR21, where RA is previously defined and R21 is selected from
(i) alkyl of one to ten carbons optionally substituted with 1 or 2 substituents selected from
aryl and
cycloalkyl of three to ten carbons,
(ii) aryl, and
(iii) cycloalkyl of three to ten carbons,
(k) alkenyl of two to ten carbons,
(l) heterocycle,
(m) aryl, and
(n) xe2x80x94NO2,
(11) xe2x80x94CN,
(12) xe2x80x94CHO,
(13) halo, and
(14) xe2x80x94B(ORA)(ORB);
provided that when R1, R2, R3, R4, and R5 are hydrogen or absent, xe2x80x94LAxe2x80x94 is a covalent bond, and xe2x80x94LBxe2x80x94 is a covalent bond, then one of XA or XB is other than hydrogen; and
R1, R2, R3, R4, and R5 are absent or independently selected from
(1) hydrogen,
(2) alkyl of one to six carbons optionally substituted with 1 or 2 substituents independently selected from
(a) xe2x80x94OC(O)R22, where R22 is selected from
(i) alkyl,
(ii) alkoxy, and
(iii) NRARB,
(b) alkoxy,
(c) xe2x80x94OH,
(d) xe2x80x94NRARB,
(e) heterocycle, and
(f) aryl,
(3) xe2x80x94CO2R7,
(4) xe2x80x94C(O)NRARB,
(5) xe2x80x94SR23 where R23 is selected from
(a) hydrogen,
(b) alkyl of one to six carbons,
(c) aryl optionally substituted with 1 or 2 substituents selected from
(i) alkyl of one to six carbons and
(ii) halo,
(6) xe2x80x94NRARB,
(7) halo,
(8) alkoxy,
(9) perfluoroalkyl of one to three carbons,
(10) xe2x80x94OH, and
(11) heterocycle,
provided that when E, F, and Y are carbon, G is nitrogen, Z is sulfur, xe2x80x94LAxe2x80x94 is a covalent bond, and XA is halo, R1 is other than xe2x80x94CO2R7.
In another embodiment of the invention are disclosed methods of treating diseases comprising administering an effective amount of a compound having Formula I.
In yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds of Formula I.
The term xe2x80x9calkanoylxe2x80x9d as used herein refers to an alkyl group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a monovalent straight or branched chain group of 2-12 carbon atoms containing at least one carbon-carbon double bond derived from an alkene by the removal of one hydrogen atom.
The term xe2x80x9calkenylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of 2-10 carbon atoms containing a carbon-carbon double bond derived from an alkene by the removal of two hydrogen atoms.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to an alkoxy group attached to the parent molecular group through another alkoxy group.
The term xe2x80x9calkoxycarbonyloxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyloxy group, as defined herein.
The term xe2x80x9calkoxycarbonyloxymethylene,xe2x80x9d as used herein, refers to an alkoxycarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.
The term xe2x80x9calkylxe2x80x9d as used herein refers to a saturated straight or branched chain group of 1-20 carbon atoms derived from an alkane by the removal of one hydrogen atom.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyloxy group, as defined herein.
The term xe2x80x9calkylcarbonyloxymethylene,xe2x80x9d as used herein, refers to an alkylcarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.
The term xe2x80x9calkylene,xe2x80x9d denotes a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2CH2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, and the like.
The term xe2x80x9camino,xe2x80x9d as used herein, refers to a xe2x80x94NR80R81 group, where R80 and R81 are independently selected from hydrogen and alkyl.
The term xe2x80x9caminocarbonyl,xe2x80x9d as used herein, refers to an amino group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term xe2x80x9caminocarbonyloxy,xe2x80x9d as used herein, refers to an aminocarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
The term xe2x80x9caminocarbonyloxymethylene,xe2x80x9d as used herein, refers to an aminocarbonyloxy group, as defined herein, appended to the parent molecular moiety through a methylene group, as defined herein.
The term xe2x80x9carylxe2x80x9d refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane or cyclopentene ring. The aryl groups of this invention can be optionally substituted.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarbonyloxy,xe2x80x9d as used herein, refers to a carbonyl group as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a monovalent saturated cyclic hydrocarbon group of 3-12 carbons derived from a cycloalkane by the removal of a single hydrogen atom.
The term xe2x80x9cethylenedioxy,xe2x80x9d as used herein, refers to a xe2x80x94O(CH2)2Oxe2x80x94 group wherein the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through one carbon atom forming a 5 membered ring or the oxygen atoms of the ethylenedioxy group are attached to the parent molecular moiety through two adjacent carbon atoms forming a six membered ring.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to F, Cl, Br, or I.
The term xe2x80x9cheterocyclexe2x80x9d represents a represents a 4-, 5-, 6-or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. The 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds. The term xe2x80x9cheterocyclexe2x80x9d also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fuised to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or another monocyclic heterocyclic ring. Heterocycles include acridinyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxadiazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, quinoxaloyl, tetrahydrofluryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiomorpholinyl, triazolyl, and the like.
Heterocyclics also include bridged bicyclic groups where a monocyclic heterocyclic group is bridged by an alkylene group such as 
and the like.
Heterocyclics also include compounds of the formula 
where X* is selected from xe2x80x94CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94 and xe2x80x94Oxe2x80x94, and Y* is selected from xe2x80x94xe2x80x94C(O)xe2x80x94 and xe2x80x94(C(Rxe2x80x3)2)vxe2x80x94, where Rxe2x80x3 is hydrogen or alkyl of one to four carbons, and v is 1-3. These heterocycles include 1,3-benzodioxolyl, 1,4-benzodioxanyl, and the like. The heterocycle groups of this invention can be optionally substituted.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to xe2x95x90O.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to xe2x80x94Oxe2x80x94.
The term xe2x80x9cmethylene,xe2x80x9d as used herein, refers to a xe2x80x94CH2xe2x80x94 group.
The term xe2x80x9cperfluoroalkylxe2x80x9d as used herein refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
The term xe2x80x9cphenylxe2x80x9d as used herein refers to a monocyclic carbocyclic ring system having one aromatic ring. The aryl group can also be fused to a cyclohexane or cyclopentane ring. The phenyl groups of this invention can be optionally substituted.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, represents compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
The term xe2x80x9cspiroalkylxe2x80x9d as used herein refers to an alkylene group wherein two carbon atoms of the alkylene group are attached to one carbon atom of the parent molecular group thereby forming a carbocyclic ring of three to eleven carbon atoms.
The term xe2x80x9ctautomerxe2x80x9d as used herein refers to a proton shift from one atom of a molecule to another atom of the same molecule wherein two or more structurally distinct compounds are in equilibrium with each other.
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to an alkyl group attached to the parent molecular group through a sulfur atom.
Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols xe2x80x9cRxe2x80x9d or xe2x80x9cS,xe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers are designated (xc2x1). Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Geometric isomers can exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the Z or E configuration wherein the term xe2x80x9cZxe2x80x9d represents substituents on the same side of the carbon-carbon double bond and the term xe2x80x9cExe2x80x9d represents substituents on opposite sides of the carbon-carbon double bond. The arrangement of substituents around a carbocyclic ring are designated as cis or trans wherein the term xe2x80x9ccisxe2x80x9d represents substituents on the same side of the plane of the ring and the term xe2x80x9ctransxe2x80x9d represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated cis/trans.
Tautomers can also exist in the compounds of the present invention. The present invention contemplates tautomers due to proton shifts from one atom to another atom of the same molecule generating two distinct compounds that are in equilibrium with each other.
Compounds of the present invention include, but are not limited to
methyl 2-[(6-ethylthieno[2,3-d]pyrimidin-4-yl)thio]acetate,
6-ethyl-4-[(4-methylphenyl)thio]thieno[2,3-d]pyrimidine,
6-ethyl-4-(2-pyridinylthio)thieno[2,3-d]pyrimidine,
6-ethyl-4-[(2-methylethyl)thio]thieno[2,3-d]pyrimidine,
6-ethyl-4-[(phenylmethyl)thio]thieno[2,3-d]pyrimidine,
6-ethyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]thieno[2,3-d]pyrimidine,
ethyl 6-ethyl-4-[(4-methylphenyl)thio]thieno[2,3-d]pyrimidine-6-carboxylate,
6-ethyl-N-(phenylmethyl)thieno[2,3-d]pyrimidin-4-amine,
6-ethyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)thieno[2,3-d]pyrimidin-4-amine,
4-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-6-ethyl-2-(phenylmethyl)thieno[2,3-d]pyrmidine,
4-chloro-6-ethyl-2-(phenylmethyl)thieno[2,3-d]pyrimidine,
4-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-6-ethyl-2-(phenylmethyl)thieno[2,3-d]pyrimidine,
7-methyl-4-[(4-methylphenyl)thio]thieno[3,2-d]pyrimidine,
7-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]thieno[3,2-d]pyrimidine,
7-methyl-4-[[5-(methylthio)-1,3,4-thiadiazol -2-yl]thio]thieno[3,2-d]pyrimidime,
4-[(5-amino-1,3,4-thiadiazol-2-yl)thio]-7-methylthieno[3,2-d]pyrimidine,
7-methyl-N-[(4-(methylthio)phenyl]thieno[3,2-d]pyrimidin-7-amine,
7-methyl-4-[(4-methylphenyl)thio]thieno[3,2-d]pyrimidine-6-carboxamide,
methyl 4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxylate,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxylic acid,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-(2-pyridinylthio)thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-chlorophenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
N-methoxy-N-methyl-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
N-methoxy-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
N-(4-chlorophenyl)-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxaldehyde,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxaldehyde, O-methyloxime,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxaldehyde, O-(phenylmethyl)oxime,
2-[[[4-[(4-methylphenyl)thio]thieno[2,3-c]pyridin-2-ylmethylene]amino]oxy]acetic acid,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxaldehyde, O-phenyloxime,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxaldehyde, oxime,
2-[[[4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-ylmethylene]-amino]oxy]acetamide,
(E)-3-[(4-methylphenyl)thio]thieno[2,3-c]pyridin-2-yl]-2-propenamide,
1-[4-[(4-methylphenyl)thio]thieno[2,3-c]pyridin-2-yl]ethanone,
2-benzoyl-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine,
2-ethyl-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine,
1-[4-[(4-methylphenyl)thio]thieno[2,3-c]pyridin-2-yl]ethanone, oxime,
N-(2,3-dihydroxypropyl)-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxylic acid, hydrazide,
N2-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridin-2-yl]carbonyl]-N6-[(nitroamino)iminomethyl]-L-lysine, methyl ester,
N-(aminoiminomethyl)-4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-carbothioamide,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine,
methyl 4-[(2-methoxy-2-oxoethyl)thio]thieno[2,3-c]pyridine-2-carboxylate,
4-[(2-amino-2-oxoethyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-bromophenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-(phenylthio)thieno[2,3-c]pyridine-2-carboxamide,
4-[[4-(trifluoromethyl)phenyl]thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(2-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(3-methylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(3,4-dimethylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(3,5-dimethylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(2,4-dimethylphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(2-methyl-3-furanyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[[(4-chlorophenyl)methyl]thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(3,4-dichlorophenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-methoxyphenyl)thio]thieno[2,3-c]pyridine-2-carboxamide,
4-(cyclohexylthio)thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-methylphenyl)thio]-N-[3-(4-morpholinyl)propyl]thieno[2,3-c]pyridine-2-carboxamide,trifluoromethylacetate salt,
4-[(4-methylphenyl)sulfinyl]thieno[2,3-c]pyridine-2-carboxamide,
methyl 4-[(4-methylphenyl)sulfinyl]thieno[2,3-c]pyridine-2-carboxylate,
4-(4-methylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
methyl 4-(4-methylphenoxy)thieno[2,3-c]pyridine-2-carboxylate,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
methyl 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylate,
4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-octylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(1-methylethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-(2-bromo-4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-ethylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-ethenylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(1,2-dihydroxyethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[2-(2-propenyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[2-(2,3-dihydroxypropyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide, 1-oxide,
4-[3-(pentadecyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(3-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-t-butylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chloro-3-methylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chloro-2-methylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-methoxyphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
ethyl 3-[[2-(aminocarbonyl)thieno[2,3-c]pyridin-4-yl]oxy]benzoate,
4-phenoxythieno[2,3-c]pyridine-2-carboxamide,
4-(3-bromophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-fluorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(3,5-dimethylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(3-chloro-4-methylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-iodophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-(methoxymethyl)phenoxy)thieno[2,3-c]pyridine-2-carboxamide,
2-(aminocarbonyl)-4-(4-chlorophenoxy)thieno[2,3-c]pyridinium, iodide,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid,
N-(4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl)-O-(3-tetrahydrofuranyl)carbamate,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-methanol,
(E)-3-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-2-propenoic acid,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxaldehyde,
(E)-3-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-2-propenamide,
4-bromothieno[2,3-c]pyridine-2-carboxamide,
methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate,
4-chlorothieno[2,3-c]pyridine-2-carboxamide,
4-[4-(trifluoromethyl)phenyl]thieno[2,3-c]pyridine-2-carboxamide,
methyl 4-[4-(trifluoromethyl)phenyl]thieno[2,3-c]pyridine-2-carboxylate,
N-methyl-4-[4-(trifluoromethyl)phenyl]thieno[2,3-c]pyridine-2-carboxamide,
4-phenylthieno[2,3-c]pyridine-2-carboxamide,
methyl 4-phenylthieno[2,3-c]pyridine-2-carboxylate,
4-([1,1xe2x80x2-biphenyl]-4-ylthio)thieno[2,3-c]pyridine-2-carboxamide,
4-(5-formyl-2-furanyl)thieno[2,3-c]pyridine-2-carboxamide,
ethyl 4-[[2-(aminocarbonyl)thieno[2,3-c]pyridin-4-yl]oxy]benzoate,
4-[[2-(aminocarbonyl)thieno[2,3-c]py idin-4-yl]oxy]benzoic acid,
4-(1-phenylethenyl)thieno[2,3-c]pyridine-2-carboxamide,
methyl 4-(1-phenylethenyl)thieno[2,3-c]pyridine-2-carboxalate,
4-[(4-methylphenyl)thio]thieno[2,3-c]pyridine-2-methanol,
4-(4-Chlorophenoxy)-N-methylthieno[2,3-c]pyiidine-2-carboxamide,
4-(4-chlorophenoxy)-N,N-dimethylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N,N-diethylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-cyclopropylthieno[2,3-c]pyridine-2-carboxamide,
1-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]pyrrolidine,
1-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]piperidine,
4-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]morpholine,
1-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]-4-methylpiperazine,
1-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]-4-phenyllpiperazine,
1-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]-4-(phenylmethyl)-piperazine,
1-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]-4-(2-pyridinyl)-piperazine,
4-(4-chlorophenoxy)-N-(2-hydroxyethyl)lthieno[2,3-c]pyridine-2-carboxamide,
4-[[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl]-N-(1-methylethyl)-1-piperazineacetamide, trifluoroacetate salt,
4-(4-chlorophenoxy)-N-[1-(hydroxymethyl)ethyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-[1, 1-bis(hydroxymethyl)ethyl]thieno[2,3-c]pyridine-2-carboxamide,
(D,L)-4-(4-chlorophenoxy)-N-(2-hydroxypropyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-[2-(4-morpholinyl)ethyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-sulfonamide,
4-[(4-methylphenyl)methyl]thieno[2,3-c]pyridine-2-carboxamide,
methyl 4-[(4-methylphenyl)methyl]thieno[2,3-c]pyridine-2-carboxylate,
4-(4-morpholinyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide, N-oxide,
methyl (4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid, N-oxide,
4-(4-chlorophenoxy)-2-(2-methoxyphenyl)thieno[2,3-c]pyridine,
4-(4-Chlorophenoxy)thieno[2,3-c]pyridine,
4-(4-Chlorophenoxy)-3-methylthieno[2,3-c]pyridine-2-carboxamide,
Methyl 4-(4-chlorophenoxy)-3-methylthieno[2,3-c]pyridine-2-carboxylate,
4-(4-Chlorophenoxy)-3-hydroxythieno[2,3-c]pyridine-2-carboxamide,
methyl 4-(4-chlorophenoxy)-3-hydroxythieno[2,3-c]pyridine-2-carboxylate,
4-(4-Chlorophenoxy)-3-(1-methylethoxy)thieno[2,3-c]pyridine-2-carboxamide,
3-bromo-4-(4-chlorophenoxy)thieno[2,3-c]pyridine,
4-(4-Chlorophenoxy)thieno[2,3-c]pyridine-3-carboxylic acid,
4-(4-Chlorophenoxy)thieno[2,3-c]pyridine-3-carboxamide,
3-amino-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
methyl 3-amino-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylate,
3-amino-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid,
4-[(4-methylphenyl)thio]thieno[2,3-b]pyridine,
4-[(4-methylphenyl)thio]thieno[2,3-b]pyridine-2-carboxamide,
4-chloro-N-(4-chlorophenyl)thieno[2,3-b]py dine-5-carboxamide,
ethyl 4-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]thieno[2,3-b]pyridine-5-carboxylate,
7-[(4-methylphenyl)thio]thieno[3,2-b]pyridine-2-carboxamide,
methyl 6-[(4-methylphenyl)thio]thieno[2,3-b]pyridine-2-carboxylate,
methyl 3-amino-6-chlorothieno[2,3-b]pyridine-2-carboxylate,
6-[(4-methylphenyl)thio]thieno[2,3-b]pyridine-2-carboxamide,
2-bromo-4-[(4-methylphenyl)thio]thieno[3,2-c]pyridine,
4-[(4-methylphenyl)thio]thieno[3,2-c]pyridine-2-carboxamide,
4-[(4-methylphenyl)thio]thieno[3,2-c]pyridine-2-carbonitrile,
4-(4-Methylphenoxy)thieno[3,2-c]pyridine-2-carboxamide,
4-(4-Methylphenoxy)thieno[3,2-c]pyridine-2-carbonitrile,
7-(4-methylphenoxy)oxazolo[5,4-c]pyridine-2-carboxamide,
methyl 7-(4-methylphenoxy)oxazolo[5,4-c]pyridine-2-carboxylate,
7-(4-methylphenoxy)[1,3]thiazolo[5,4-c]pyridine-2-carboxamide,
methyl 7-(4-methylphenoxy)[1,3]thiazolo[5,4-c]pyridine-2-carboxylate,
7-(4-methylphenoxy)-3H-imidazo[4,5-c]pyridine-2-carboxamide,
methyl 7-(4-methylphenoxy)-3H-imidazo[4,5-c]pyridine-2-carboxylate,
4-(4-chlorophenoxy)thieno[2,3-d]pyridazine-2-carboxamide,
4-(4-chlorophenoxy)thieno[2,3-d]pyridazine-2-carboxylic acid,
7-(4-chlorophenoxy)thieno[3,2-c]pyridine-2-carbaimide,
7-(4-chlorophenoxy)thieno[3,2-c]pyridine-2-carboxylic acid,
4-(4-chlorophenoxy)thieno[2,3-c]pydine-2-carbothioamide,
4-(4-chlorophenoxy)-N-ethylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-(2,3-dihydroxypropy)thieno[2,3-c]pyfidine-2-carboxamide,
4-(4-bromophenoxy)-N-(2,3-dihydroxypropyl)thieno[2,3-c]pyridine-2-carboxamide,
N-(2-hoo ty)4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxhiamide,
4-(4-bromophenoxy)-N-(2-hydroxyethyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(2-bromo-4-chlorophenoxy)-N-(2-hydroxyethyl)thieno[2,3-c]pyridine-2-carboxamide,
N-(2-hydroxyethyl)-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-(2-aminoethyl)-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-hydroxy thieno[2,3-c]pyndine-2-carboxamide,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carbohydrazide,
4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carbohydrazide,
4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carbohydrazide,
4-(4-chlorophenoxy)-N-hydroxythieno[2,3-c]pyridine-2-carboxamide,
2-({[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl}amino)acetic acid,
N-(2-amino-2-oxoethyl)-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
N-(2-amino-2-oxoethyl)-4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
(2S)-2-({[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl}amino)-3-hydroxypropanoic acid,
N-[(1 S)-2-amino-1-(hydroxymethyl)-2-oxoethyl]-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
(2R)-2-({[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl}amino)-3-hydroxypropanoic acid,
(2R)-2-({[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl}amino)propanoic acid,
4-(4-chlorophenoxy)-N-[(1R)-1-methyl-2-(methylamino)-2-oxoethyl]thieno[2,3-c]pyridine-2-carboxamide,
(2S)-2-({[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]carbonyl}amino)propanoic acid,
4-(4-chlorophenoxy)-N-[(1S)-i -methyl-2-(methylamino)-2-oxoethyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-[(1 R)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-[(1S)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(3-pyridinyloxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenoxy)-N,N-dimethylthieno[2,3-c]pyridine-2-carboxamide,
N,N-dimethyl-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chloro-3-fluorophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-chloro-3-fluorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chloro-3-ethylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(3-fluorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(2,3-difluorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(2,3-difluorophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(3-fluorophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-(2,3,4-trifluorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(2,3,4-trifluorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[3-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N,N-dimethyl-4-(4-vinylphenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-cyanophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-cyanophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-aminophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(acetylamino)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(4-morpholinyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(hydroxymethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(hydroxymethyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-[4-(methoxymethyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-{4-[(2-methoxyethoxy)methyl]phenoxyl thieno[2,3-c]pyridine-2-carboxamide,
4-{4-[(2-methoxyethoxy)methyl]phenoxy}-N-methylthieno[2,3-c]pyridine -2-carboxamide,
4-(4-{[2-(2-methoxyethoxy)ethoxy]methyl}phenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-{[2-(2-methoxyethoxy)ethoxy]methyl}phenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-{4-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenoxyl thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-{4-[(tetrahydro-2H-pyran-2-y loxy)methyl]phenoxy}thieno[2,3-c]pyridine-2-carboxamide,
4-{[2-(aminocarbonyl)thieno[2,3-c]pyridin-4-yl]oxy}benzyl 2-ftiroate,
4-[4-({[(2R,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}methyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-acetylphenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-[4-(4-morpholinylcarbonyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(4-morpholinylcarbonyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-[4-({[2-(4-morpholinyl)ethyl]amino}carbonyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-({[2-(4-morpholinyl)ethyl]amino}carbonyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-{4-[(E)-3-(4-morpholinyl)-3-oxo-1-propenyl]phenoxy}thieno[2,3-c]pyridine-2-carboxamide,
4-[4-((E)-3-{[2-(4-morpholinyl)ethyl]amino}-3-oxo-1-propenyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-((E)-3-{[2-(4-morpholinyl)ethyl] amino }-3-oxo-1-propenyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-{(E)-3-[(2,3-dihydroxypropyl)amino]-3-oxo-1-propenyl}phenoxy)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-{(E)-3-[(2,3-dihydroxypropyl)amino]-3-oxo-1-propenyl }phenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-[4-((E)-3-{[2-(1H-imidazol-4-yl)ethyl]amino}-3-oxo-1-propenyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-{4-[(E)-3-({2-[bis(2-hydroxyethyl)amino]ethyl}amino)-3-oxo-1-propenyl]phenoxy}-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-{4-[(E)-3-({2-[bis(2-hydroxyethyl)amino]ethyl}amino)-3-oxo-1-propenyl]phenoxy}thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(1H-imidazol-1-yl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(1 1H-pyrazol-1-yl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide ,
N-methyl-4-[4-(1H-12,4-triazol-1-yl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-{4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy}thieno[2,3-c]pyridine-2-carboxamide,
4-[4-(4,5-dihydro-(1H-imidazol-2-yl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(2-thienyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-([1,1xe2x80x2-biphenyl]-4-yloxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(methyl-1H-imidazol-5-yl)phenoxy]thieno[2,3-c]pyridine-2-carb oxamide,
4-{4-([1,-(hydroxymethyl)cyclopropyl]phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-[4-(1-{2-(2-ethoxyethoxy)ethoxy]methyl}cyclopropyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-[4-(trifluoromethoxy)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
5-{4-[4-(1-{[2-(2-ethoxyethoxy)ethoxy]methyl}cyclopropyl)phenoxy]thieno[2,3-c]pyridin-2-yl}-1,3,4-oxadiazol-2-amine,
4-[4-(1,1-difluoro-2-hydroxyethyl)phenoxy]-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-{2-[2-(2-ethoxyethoxy)ethoxy]-1,1-difluoroethyl}phenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-6-{[(2,2-dimethylpropanoyl)oxy]methyl}-2-[(methylamino)carbonyl]thieno[2,3-c]pyridin-6-ium,
4-(4-bromophenoxy)-6-{[(2,2-dimethylpropanoyl)oxy]methyl}-2-[(methylamino)carbonyl]thieno[2,3-c]pyridin-6-ium,
2-(aminocarbonyl)-4-(4-chlorophenoxy)-6-{[(isopropoxycarbonyl)oxy]methyl}thieno[2,3-c]pyridin-6-ium,
4-(benzyloxy)thieno[2,3-c]pyridine-2-carboxamide,
4-[(4-chlorophenyl)(hydroxy)methyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorobenzoyl)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
N4-(4-chlorophenyl)thieno[2,3-c]pyridine-2,4-dicarboxamide,
[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]methanol,
4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carbaldehyde,
4-(4-chlorophenoxy)thieno[2,3,-c]pyndine-2-carbaldehyde oxime,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carbaldehyde O-methyloxime,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-l-ethanone O-methyloxime,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1-ethanone O-methyloxime,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1-ethanone O-methylox,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1-ethanone oxime,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1-ethanone oxime,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1-propanone,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1-propanone oxime,
2-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-N-methoxy-N-methyl-2-oxoacetamide,
4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carbonitrile,
4-(4-chlorophenoxy)-Nxe2x80x2-hydroxythieno[2,3-c]pyridine-2-carboximidamide,
4-(4-chlorophenoxy)-Nxe2x80x2-cyanothieno[2,3-c]pyridine-2-carboximidamide,
[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl](2-nitrophenyl)methanol,
[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl](2-nitrophenyl)methanone,
(2-aminophenyl)[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methanone,
(2-aminophenyl)[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methanol,
[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl](3-nitrophenyl)methanol,
(3-aminophenyl)[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methanone,
(3-aminophenyl)[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methanol,
4-(4-bromophenoxy)-2-vinylthieno[2,3-c]pyridine,
1-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,2-ethanediol,
1-[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]-1,2-ethanediol,
[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methanamine,
[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methyl carbamate,
N-{[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]methyl}urea,
(E)-3-[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]-2-propenamide,
(E)-3-[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]-N-methyl-2-propenamide,
3-[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]-2,3-dihydroxy-N-methylpropanamide,
3-[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]-2,3-dlhydroxypropanamide,
4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-ylamine,
4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-ylformamide,
N-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]urea,
N-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2yl]-Nxe2x80x2-methylthiourea,
4-(4-chlorophenoxy)-N-methylthieno[2,3-c]pyridine-2-sulfonamide,
4-(4-chlorophenoxy)-N-(2,3-dihydroxypropyl)thieno[2,3-c]pyridine-2-sulfonamide,
4-(4-chlorophenoxy)-N-(2-hydroxyethyl)thieno[2,3-c]pyridine-2-sulfonamide,
4-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]phenol,
3-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]aniline,
4-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]aniline,
4-(4-chlorophenoxy)-2-(5-nitro-2-pyridinyl)thieno[2,3-c]pyridine,
6-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-3-pyridinamine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-2-pyridinamine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-13,4-oxadiazol-2-amine,
5-[4-(4-bromophenoxy)thieno[2,3-c]pyridin-2-yl]-1,3,4-oxadiazol-2-ylamine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-4H-1,2,4-triazol-3-amine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,3,4-thiadiazol-2-amine,
4-(4-chlorophenoxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)thieno[2,3-c]pyridine,
5-{4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridin-2-yl}-1,3,4-oxadiazol-2-amine,
4-(4-chlorophenoxy)-2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]thieno[2,3-c]pyridine,
4-(4-chlorophenoxy)-2-(2-methyl-2H-1,2,3,4-tetraazol-5-yl)thieno[2,3-c]pyridine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-4-methyl-4H-1,2,4-triazol-3-amine
4-(4-chlorophenoxy)-2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]thieno[2,3-c]pyridine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,2,4-oxadiazol-3-amine,
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-N-methyl-1,3,4-thiadiazol-2-amine,
4-(4-chlorophenoxy)-2-(1,2,4-oxadiazol-3-yl)thieno[2,3-c]pyridine,
2-(1,3,4-oxadiazol-2-yl)-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine,
3-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,2,4-oxadiazol-5-amine,
2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine,
methyl 2-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,3-thiazole-4-carboxylate,
2-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,3-thiazole-4-carboxamide,
tert-butyl 2-[4-(4-chlorophenoxy )thieno[2,3-c]pynidin-2-yl]-1,3-thiazol-4-ylcarbamate,
2-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin -2-yl]-1,3-thiazol -4-amine,
4-(4-chlorophenoxy)-2-(1,3-oxazol-2-yl)thieno[2,3-c]pyridine,
4-(4-chlorophenoxy)-2-(1H-imidazol-2-yl)thieno[2,3-c]pyridine,
4-chloro-3-methylthieno[2,3-c]pyridine-2-carboxamide,
3-amino-4-chlorothieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N,3-dimethylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenoxy)-3-methylthieno[2,3-c]pyridine-2-carboxamide,
7-chloro-4-(4-chlorophenoxy)-3-methylthieno[2,3-c]pyridine-2-carboxamide,
tert-butyl 2-(aminocarbonyl)-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-3-carboxylate,
N-methyl-4-(4-toluidino)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chloroanilino)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
N-methyl-4-(4-morpholinyl)thieno[2,3-c]pyridine-2-carboxamide,
7-chloro-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
7-chloro-4-(4-chlorophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
7-chloro-4-(4-chlorophenoxy)-N-(2-hydroxyethyl)thieno[2,3-c]pyridine-2-carboxamide,
7-bromo-4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide,
7-bromo-4-(4-chlorophenoxy)-N-methylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenoxy)-7-chlorothieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenoxy)-7-chloro-N-methylthieno[2,3-c]pyridine-2-carboxamide,
7-chloro-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
7-chloro-N-methyl-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
7-chloro-N-(2-hydroxyethyl)-4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N,7-dimethylthieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-7-methoxythieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)-N-methyl-7-(methylamino)thieno[2,3-c]pyridine-2-carboxamide,
7-(4-methylphenoxy) [1,3]thiazolo[5,4-c]pyridine-2-carboxamide,
N-methyl-7-(4-methylphenoxy)[1,3]thiazolo[5,4-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)furo[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenoxy)furo[2,3-c]pyridine-2-carbothioamide,
4-[(E)-2-phenylethenyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(4-chlorophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-[3-(trifluoromethyl)phenyl]thieno[2,3-c]pyridine-2-carboxamide,
4-(3-chlorophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-bromophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(3-aminophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(3,5-dichlorophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(2,4-dichlorophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(3,4-dichlorophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(2,4-difluorophenyl)thieno[2,3-c]pyridine-2-carboxamide,
4-(4-fluorophenyl)thieno[2,3-c]pyridine-2-carboxamide, and
4-(4-bromophenoxy)-5-chlorothieno[2,3-c]pyridine-2-carboxamide.
Pooled primary human umbilical vein endothelial cells (HtVEC""s) (Clonetics) between passages 3 and 7 were plated in 96-well plates (Costar), 100 xcexcL/well, 5xc3x97104 cells/mL in Clonetics EBM/2% FBS/EGF/Bovine brain extract/gentamicin in the absence of hydrocortisone. The following day, compounds of the invention were added in 10 xcexcL/well medium, and the plates were incubated at 37xc2x0 C. 24 hours after compound addition, TNF (Gibco/BRL) in 10 xcexcL/well medium was added to a final concentration of 5 ng/mL, and the cells were incubated an additional 6 hours at 37xc2x0 C. Then media was removed, and the plates were washed once with D-PBS (Gibco/BRL) and treated with primary antibodies (Becton Dickinson, City), 100 xcexcL/well in D-PBS/2% BSA (Sigma)/0.01% azide. Primary antibodies at an initial concentration of 1 mg/mL were used at the following dilutions: anti-ELAM-1, 1:2000, anti-ICAM-1, 1:2000 and anti-VACM-1, 1:3000. Plates were stored overnight at 4xc2x0 C., washed 3 times with D-PBS, and treated with secondary antibody (Jackson Labs), 100 xcexcL/well 1:8000 dilution HRP-conjugated donkey anti-mouse IgG(H+L) in D-PBS/2%BSA. Plates were incubated a minimum of 1 hour at room temperature, washed 3 times with D-PBS and treated with 100 xcexcL of orhto-phenylene diamine-2 HCl reagent per well. Plates were developed approximately 15 minutes and neutralized with 100 xcexcL/well 1N sulfuric acid. Absorbance was read at 490 nm. Inhibitory potencies for representative compounds of the invention are shown in Table 1.
Thus the compounds of the present invention act as antiinflammatory agents with potencies below 1 xcexcM and are therefore useful for treating inflammatory diseases.
The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term xe2x80x9cparenteralxe2x80x9d administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. By xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like. Preferred salts of the compounds of the invention include phosphate, tris and acetate.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
Abbreviations which have been used in the descriptions of the schemes and the examples that follow are: BH3 for borane, BH3xc2x7DMS for borane dimethylsulfide complex, BINAP for 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, BF3OEt2 for boron trifluoride diethyl ether complex, n-BuLi for n-butyllithium, CCl4 for carbon tetrachloride, Cs2CO3 for cesium carbonate, DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene, DMA for N,N-dimethylacetamide, DIBAL for diusobutylaluminum hydride, DME for dimethoxyethane, DMF for N,N-dimethylformamide, DMSO for dimethylsulfoxide, DIPEA for diisopropylethylamine, DPPA for diphenylphosphoryl azide, EDCI or EDC for 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, Et3N for triethylamine, Et2O for diethyl ether, EtOAc for ethyl acetate, EtOH for ethanol, K2CO3 for potassium carbonate, LiAlH4 for lithium aluminum hydride, LDA for lithium diisopropylamide, MeOH for methanol, NaOMe for sodium methoxide, NaOH for sodium hydroxide, HCl for hydrochloric acid, NMP for 1-methyl-2-pyrrolidinone, H2/Pd for hydrogen and a palladium catalyst, iPrOH for isopropyl alcohol, PPh3 for triphenylphosphine, THF for tetrahydrofuran, THP for tetrahydropyran, TFA for trifluoroacetic acid, and pyBOP for benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention can be prepared. Further, all citations herein are incorporated by reference. 
Scheme 1 shows the preparation of thieno[2,3-d]pyrimidines from esters of general fornula 1 by published procedures. 4-Chlorothieno[2,3-d]pyrimidines of general formula 3 were substituted with thiols to provide 4-thioethers of general formula 4 or substituted with amines to provide 4-aminothieno[2,3-d]pyrimidines of general formula 5. 
Scheme 2 shows the preparation of 2-carboxy-substituted thieno[2,3-d]pyrimidines. Pyrimidinones of general formula 1 weres reacted with phosphoryl chloride to produce 4-chloro pyrimidines of general formula 6, which were then substituted with thiols to provide thioethers of general formula 7. 
Scheme 3 shows the preparation of thieno[3,2-d]pyrimidines derived from chloropyrimidines of general formula 8. Substitution of the chlorides with thiols provided thioethers of general formula 9, and substitution of the chlorides with amines provided aminopyrimidines of general formula 10. 
Analogs having 2-carboxamide groups on the thieno[3,2-d]pyrimidine were prepared as shown in Scheme 4. The thiophene-2-position was deprotonated with a strong base such as lithium diisopropylamide, and the corresponding carbanion was treated with carbon dioxide to provide acids of general formula 11. The acids were converted to the corresponding amides of general formula 12 through the intermediate acid chlorides. 
Scheme 5 shows the preparation of 6-alkyl substituted thieno[2,3-d]pyrimidines with alkylthio groups at the 4-position. Using known procedures, 2-aminothiophene 13 was acylated to provide amnide 14 which was cyclized to provide thienopyrimidinone 15. The pyrimidinone was converted to chloride 16 and further to thio ether 17 by standard procedures. 
The general process for preparing 2,4-disubstituted thieno[2,3-c]pyridines is shown in Scheme 6. Commercially available 3,5-dichlorpyridine was treated with strong base such as lithium dilsopropylamide in an anhydrous solvent at low temperature followed by reaction with methyl formate (or alternatively, dimethylformamide) to provide the known pyridine-4-carboxaldehyde 18. Aldehyde 18 was then substituted with one equivalent of thiol (R1=substituted or unsubstituted aryl, alkyl, or heterocyclic) to produce chloroaldehyde of general formula 19. Treatment of 19 with methyl thioglycolate and a base such as cesium carbonate or potassium carbonate provided the 4-thioether [2,3-c]-thienopyridine esters of general formula 20. The esters were converted to the corresponding acids of general formula 21 by basic hydrolysis, for example using lithium, sodium, or potassium hydroxide in a mixture of water and alcohol or tetrahydrofuran. Acids of general formula 21 may also be converted to amides of general formula 22 or 23 through the intermediate acid chlorides by treatment first with oxalyl chloride or thionyl chloride, then with the amine of choice (R2, R3 can be substituted or unsubstituted alkyl, aryl, heterocyclic). Alternatively, aicds 21 may be converted to amides 22 or 23 by other coupling methods, such as carbodiimide (for example, N-ethyl-Nxe2x80x2-(3-dimethylamino)propyl carbodiimide hydrochloride (EDC)), mixed anhydrides (derived from pivaloyl chloride or isobutyl chloroformate treatment), and active esters (for example, derived from N-hydroxysuccinimide, p-nitrophenol). 
Scheme 7 illustrates the analogous preparation of 4-ether-substituted thienopyridines of general formula 30. Aldehyde 18 was substituted with alcohols (R1=substituted or unsubstituted aryl, heterocyclic) under basic conditions (for example, potassium tert-butoxide or cesium carbonate in anhydrous tetrahydrofuran or dimethylformamide) to give pyridine-ethers of general formula 24, and then further reacted with methyl thioglycolate to provide the thieno[2,3-c]pyridine esters of general formula 25. These esters may be converted to the corresponding primary amides of general formula 26 by heating in methanolic ammonia solution. Alternatively, esters of general formula 25 may be reacted with mono or disubstituted amines in polar solvents such as dimethylformamide or methanol. Esters of general formula 25 were hydrolyzed to carboxylic acids of general formula 28 by basic hydrolysis with sodium or lithium hydroxide in aqueous methanol or tetrahydrofuran. The acids were then converted to amides of general formula 30 by reaction of the corresponding acid chlorides of general formula 29 with amines. Alternatively, the acids 30 were coupled to amines by standard peptide-coupling conditions as described in Scheme 6 for amides 22 or 23. 
Similar methods may be utilized for the preparation of 4-bromothieno[2,3-c]pyridine 32, as shown in Scheme 8. 3,5-Dibromopyridine was converted to aldehyde 31 by the procedure described for preparation of compound 18 in Scheme 6. Reaction of 31 with methyl thioglycolate, for example in the presence of cesium carbonate in DMF, produced 4-bromothieno[2,3-c]pyridine ester 32. Bromide 32 served as starting material for the preparation of 4-aryl, heterocyclic, alkyl, or alkenyl derivatives of general formula 33, using Suzuki coupling methodology as shown. Bromide 32 may also be coupled with terminal alkynes to provide alkynyl derivatives (R1=alkynyl) following Sonogashira methodology (Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467-70). Esters of general formula 33 were converted to amides of general formula 34 by the procedures described for 26, 27 or 30 in Scheme 7. 
Scheme 9 shows the conversion of acids of general formula 21 to aldehyde or ketone-derived compounds. For example, aldehydes of general formula 36 were produced by reduction of the N-methyl-N-methoxylamides of general formula 35. The amides of general formula 35 were also reacted with Grignard reagents to produce unsymmetrical ketones of general formula 39. Aldehydes of general formula 36 and Ketones of general formula 39 were utilized for the production of oximes of general formula 37 or 40 by reaction with hydroxylamine derivatives. Aldehyde of general formula 36 were reacted with phosphoranes (or phosphonoacetate salts) to produce 2-alkenyl substituted derivatives of general formula 38. Ketones of general formula 39 were reduced to the corresponding alkanes of general formula 41 by treatment with hydrazine and strong base, such as potassium hydroxide. Analogous 2-position derivatives of thienopyridine ethers of general formula 28 in Scheme 7 would follow similar synthetic routes as described in Scheme 9. Thus, acids 28 may be converted to aldehydes, ketones, oximes, alkenes, or alkanes substitutions at the 2-position. 
Amides of general formula 34 (or 26, 27 or 30), may be converted to the corresponding thionoamides of general formula 42 by treatment with Lawesson""s reagent as shown in Scheme 10. 
As shown in Scheme 11, 4-sulfoxides of general formula 43 were produced by reaction of thioethers of general formula 20 with an oxidant such as m-chloroperoxybenzoic acid under controlled conditions. 
Alternative functionality was introduced at the 2-position of thienopyridines of general formula 44 by metallation of the 2-position, followed by reaction with appropriate electrophiles, as shown in Scheme 12. Acids of general formula 21 (LAXA=thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic) were decarboxylated at elevated temperatures (optionally in the presence of copper powder) to afford 2-unsubstituted derivatives of general formula 44. Compounds of general formula 44 were deprotonated with strong organic bases such as n-butyllithium, and then reacted with electrophiles such as borates, cyanofornates, aldehydes, or trialkyltin chlorides according to standard procedures (Masakatsu, N.; Kazuhiro, N.; Ichiro, M.; Iwao; W. Chem. Lett. 1983, 6, 905-908). 
Scheme 13 illustrates an alternative method for the preparation of 2-carboxaldehydes of general formula 36 or 47. Esters of general formula 20 or 25 (R1=thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic) were reduced to the corresponding alcohols of general formula 46 using calcium borohydride. The alcohols were then oxidized to the aldehydes using Swern conditions. The aldehydes were then reacted with Wittig reagents (for example phosphoranes to produce the acrylate derivatives of general formula 48 (Jung, M. E. and Kiankarami, M. J. Org. Chem. 1998, 63, 2968-2974). 
As shown in Scheme 14, thienopyridines of general formula 27 or 30 were alkylated on the pyridine nitrogen using alkyl iodides (or alkyl bromides or triflates) to produce the pyridinium salts of general formula 49. For example, R may be alkylcarbonyloxymethylene, aminocarbonyloxymethylene, alkoxycarbonyloxymethylene, or alkyl. Such derivatives may serve as prodrug forms of the thienopyridine amides 27 or 30. 
A variety of 2-aminothieno[2,3-c]pyridine derivatives were available starting from the 2-carboxylic acids of general formula 21 or 28, as shown in Scheme 15, wherein R1 may be thioalkoxy, alkoxy, alkyl, alkenyl, aryl, heterocyclic. Curtius rearrangement led to isocyanates of general formula 50, which were reacted with alcohols (alkyl, aryl, heterocyclic, or dialkylaminoalkyl) to provide carbamates of general formula 51. Isocyanates 50 may be reacted with amines (ammonia, primary alkyl or secondary alkyl) to provide ureas of general formula 52. Also, 50 may be reacted with alkyl or arylmagnesium halides, or alkyl lithium salts, to provide amides of general formula 53. Isocyanate 50 was hydrolyzed under aqueous conditions to produce 2-amino derivatives of general formula 54. 
Amines of general formula 54 were reacted with appropriate electrophiles to further derivative this position. Thus reaction of 54 with aryl or alkylsulfonyl chlorides (R2=alkyl, aryl, heterocyclic) or sulfamoyl chlorides, (R2=NH2, mono- or di-alkylamino) to give sulfonamides of general formula 55. Amino derivative 54 was also reacted with acyl chlorides (R2=alkyl, heterocyclic, or aryl) to produce amides of general formula 53 as shown in Scheme 16. 
Functionality present on the aryl rings attached at the 4-position of the thieno[2,3-c]pyridines may be further reacted to advantage, as illustrated in Scheme 17. For example, styryl derivative 56 was converted to the 1,2-diol 57 by treatment with osmium tetroxide under standard conditions. The 4-(4-bromophenoxy) derivative 58 underwent fascile substitution with aryl boronic acids under palladium catalysis under Suzuki conditions to provide biaryl derivatives of general formula 59. Alternatively, alkoxycarbonylation under palladium catalysis efficiently provides esters of general formula 61. 
Scheme 19 shows the use of boronic acid derivatives to functionalize the 4-position of the thieno[2,3-c]pyridines. The chemistry depicted may be applied to a broad range of aryl olefins analogous to bromostyrene 62. In the case shown, bromostyrene 62 was converted to the boronic acid 63 under standard conditions, and the boronic acid was coupled to 4-bromothienopyridine 32 under Suzuki conditions, affording the styryl analog 64. The ester 64 was converted to the amide 65 by the previously described method (Miyara, N and Suzuki, A. Chem. Rev. 1995, 95, 2457-2463). The olefinic group may then be converted to the epoxide 66, which can undergo reactions with nucleophilic reagents at the less-hindered position of the epoxide to producing analogs of general formula 67. Alternatively, styryl derivative 65 may be converted to the diol 68 by standard methods. 
Another method for introduction of substituents at the 4-position of the thieno[2,3-c]pyridines is shown in Scheme 20. Bromide 32 may be converted to the corresponding cuprate through the intermediate zinc bromide reagent, which then may be reacted with appropriate electrophiles (acid chlorides, alkyl halides, aldehydes, ketones) to afford the substituted compounds of general formula 69 (Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445-1453). 
Scheme 21 depicts the preparation of 5-halo thienopyridine derivatives, as exemplified by the preparation of the 5-chloro analog 75. Formylation of lithiated 2,3,5-trichloropyridine with methyl formate gave aldehyde 72. Displacement of the 3 and 5 chlorines with excess 4-bromophenol and reaction with methylthioglycolate gave the 5-chlorothienopyridine 74 in low yield, together with the major product 73. The 5-chloro isomer was treated with ammonia in methanol in a pressure tube to generate the amide 75. It should be noted that this chemistry may be applied using a range of phenols or hydroxy heterocyclic compounds in place of 4-bromophenol. 
The 2-position of thienopyridines was substituted with aryl, vinyl, acetylenic or alkyl groups using the procedure shown in Scheme 22. Boronic acids of general formula 79 prepared according to Scheme 12, was coupled to aryl halides under palladium catalysis to produce 2-aryl derivatives of general formula 80. 
Scheme 23 illustrates the preparation of 4-acyl derivatives of thieno[2,3-c]pyridines. Carboxylic acid 85 was converted to amide 86 via the acid chloride, then the hydroxyamide 86 underwent thionyl chloride-mediated cyclization to the oxazoline 87 (Meyers, A. I.; Stoianova, D. J. Org. Chem. 1997, 62, 5219-522 1). Palladium mediated alkoxycarbonylation of 87 yielded ester 88 (Heck, R. F.; et al. J. Org. Chem. 1974, 39, 3318). Ester 88 may be converted to the Weinreb amnide 89 by standard methods. Amide 89 was reacted with the appropriate Grignard reagents to provide the desired 4-acyl products of general formula 90. Hydrolysis of the oxazoline and conversion of the resultant carboxylic acid to the amide yields the desired products of general formula 91. 
Scheme 24 depicts a proposed method for the formation of 4-hydroxy substituted thieno[2,3-c]pyridine. Reaction of phenol 92 with dihydropyran under acidic conditions yields tetrahydropyranyl ether 93 (Grant, H. N., et al. Helv. Chim. Acta. 1963, 46, 41). Lithiation of 93 and subsequent quench with methyl formate gives aldehyde 94. Displacement of the halide with methyl thioglycolate and subsequent cyclization with cesium carbonate yields the ester 95. Removal of the tetrahydropyranyl ether with aqueous HCl gives hydroxypyridine 96, which may be converted to the amide as described previously. 
Scheme 25 proposes the use of the 4-hydroxy group for introduction of functionality to the 4-position of the thieno[2,3-c]pyridines. The 2-carboxylic acid group is first protected as the oxazoline 99 (through the intermediate amide 98), then the hydroxy group is converted to the aryl triflate 100 by standard conditions. Triflate 100 may then be converted to the N-methyl-N-methoxy amide 89 under conditions similar to that for bromide 87. It should be noted that 4-triflate 100 may serve as a coupling partner in a variety of transition-metal mediated couplings with appropriate nucleophilic partners (for example, boronic acids, boranes, alkyl or aryl-zinc reagents). 
Compounds with amino substitutions at the 3-position of the thieno[2,3-c]pyridines were prepared according to the procedures outlined in Scheme 26. Aldehyde 18 was converted to the cyanopyridine 107 by treatment with hydroxylamine under dehydrating conditions. In a manner similar to the reactions involving aldehyde 18, cyanopyridine 107 was sequentially substituted with phenols and methyl thioglycolate to provide the 3-amino thieno[2,3-c]pyridines of general formula 108. Esters of general formula 108 were then converted to amides of general formula 109 by standard procedures. 
Scheme 27 illustrates additional derivatives which can be derived from amino esters of general formula 108 or amino amides of general formula 109. For example, amino amides of general formula 109 may be treated with 1,1xe2x80x2-carbonyldiimidazole to produce cyclic imides of general formula 110. The 3-amino group was acylated (for example, with acid chlorides and weak base, or by coupling with acids using carbodiumides) to give the diamides of general formula 111. The 3-amino group may be alkylated under reductive conditions using aldehydes and a reducing agent (such as triacetoxyborohydride), to provide alkylated amines of general formula 112. 
Scheme 28 shows the preparation of compounds bearing alkyl substituents at the 3-position of the thieno[2,3-c]pyridines. Using similar chemistry to that described for compound 30,3,5-dichloropyridine was deprotonated with strong base (for example, lithium diisopropylamide), and then reacted with an acylating reagent (ester, N-methyl-N-methoxyamide, acyl pyrazole, or others) to provide ketone 113. Alternatively, the anion can be reacted with an aldehyde (for example, acetaldehyde) and then subsequently the product may be oxidized (for example, with tetrapropylammonium perruthenate) to provide ketone 113. Following the protocol outlined for example 30, the dichloroketone was reacted sequentially with phenols and then with methyl thioglycolate to provide cyclic products of general formula 114. The esters of general formula 114 may be converted to various derivatives as outlined previously. 
Scheme 29 describes a similar strategy used to obtain derivatives with alkoxy groups at the 3-position of thieno[2,3-c]pyridines. Ester 116 was substituted and cyclized to provide 3-hydroxy analogs of general formula 117. The hydroxy group may be left unsubstituted, leading to amides of general formula 118 (or other derivatives). Alternatively, hydroxy esters of general formula 117 may be alkylated by standard procedures to produce 3-alkoxy derivates of general formula 119, followed by amide formation to provide compounds of general formula 120. 
Scheme 30 shows the procedure used for the transformation of a commercially available furo[2,3-b]pyridine 121 into an amide 122. 
Scheme 31 proposes the preparation of thienopyridine derivatives containing an amide group at the 3-position. Thienopyridines of general formula 44 are halogenated using electophilic halide sources (for example, N-bromosuccinimide, I2), to produce 3-halothienopyridines of general formula 123. Metal-halogen exchange, followed by trapping with carbon dioxide, provides acids of general formula 124. The acids are converted into amides of general formula 125 by standard procedures, or may be homologated to esters of general formula 126 (for example, by the Arndt-Eisert procedure). Esters of general formula 126 may then be converted to amides or other functionality by the methods described above. 
Scheme 32 describes the methods used for the preparation of a variety of thieno[2,3-b]pyridines starting from the known 4-chloro-5-ester 127. Displacement of the chlorine of 127 proceeded with thiols in the presence of potassium carbonate to provide 4-thioethers of general formula 128. Ester 127 was also hydrolyzed to the acid 129, which was converted to amides of general formula 130 by standard coupling conditions. 
Scheme 33 shows the conversion of thioethers of general formula 128 to 2,4-disubstituted analogs. The corresponding acids of general formula 131 may be thermally decarboxylated to provide the 5-unsubstituted analogs of general formula 132. Compounds of general formula 132 were treated with strong base (for example, n-butyllithium), and reacted with carbon dioxide to provide the 2-carboxylic acids of general formula 133. The acids were then transformed into amides of general formula 134 by previously described procedures. 
Scheme 34 illustrates the preparation of thieno[3,2-b]pyridines. Chloride 135 was transformed by a similar set of conditions to that described in Scheme 33 to produce acids of general formula 139 and amides of general formula 140. 
Scheme 35 depicts the preparation of thieno[3,2-c]pyridines. Starting with thienopyridone 141, 4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-nitrile 144 was prepared according to literature methods (Eloy, F.; Deryckere, A. Bul. Soc. Chim. Belg. 1970, 79, 301; Troxler, F.; Wiskott. E. U.S. Pat. 3,998,835). Treatment of thienopyridone 144 with phosphoryl chloride at 130xc2x0 C. provided chloride 145, which upon exposure to thiols under basic conditions afforded thioethers of general formula 146. Hydrolysis of the nitrile group with polyphosphoric acid gave the corresponding amides of general formula 147. 
Scheme 36 show that ethers of general formula 149 were prepared in an analogous fashion as previously described in Scheme 35. 
Scheme 37 shows the preparation of intermediates of general formula 151 useful for the preparation of alternative 2-derivatives. Treatment of the known 2-bromo-4-chlorothieno[3,2-c]pyridine 150 with 1 equivalent of a thiol afforded 2-bromothieno[3,2-c]pyridines of general formula 151. 
Scheme 38 depicts an example of the preparation of a related class of inhibitors based on an oxazolopyridine structure. Commercially available 3-chloropyridine is oxidized to the N-oxide 152 with peracetic acid, which is then nitrated in a mixture of concentrated nitric, concentrated sulfuric, and fuming sulfuric acids to give the 4-nitro derivative 153. The chlorine in 153 is then displaced with the sodium salt of p-cresol, and the resulting biaryl ether 154 is hydrogenated (Raney nickel catalysis) to reduce both the nitro functional group and the N-oxide to give 155. The amino group of 155 is protected with an N-trimethylacetyl group, and the 5-hydroxyl group is introduced according the procedure of Chu-Moyer and Berger (J. Org. Chem. 1995, 60, 5721) by formation of the dianion of 156, quenching with trimethyl borate, and oxidation of the intermediate boronate ester followed by hydrolysis with basic hydrogen peroxide to give hydroxypyridine 157. The amide is hydrolyzed with hydrochloric acid to give 158, which is condensed with methyl oxalyl chloride to give the oxazolopyridine 158. The methyl ester in 159 was then converted to the primary amide by treatment with ammonia in methanol to give the target compound 160. 
Scheme 39 illustrates an example of the preparation of an analogous thiazolopyridine-based inhibitor. The scheme illustrates the use of para-cresol substituted pyridine as starting material, but the synthesis may be generalized to other aryl, heterocyclic, or alkyl ethers. The dianion of 4-(N-trimethylacetyl)-amino-3-(4-methylphenoxy)-pyridine is quenched with tetramethylthiuram disulfide to introduce the 5-mercapto group into the substituted pyridine ring as dithiocarbamate 161. Subsequent deprotection of the amine under acidic conditions is followed by acylation of the free aniline 162 with methyl oxalyl chloride to afford the oxalamide 163. The thiazolopyridine bicyclic core 164 is then prepared by treatment with mild acid (for example formic acid at reflux). The ester functionality was converted to the corresponding amide 165 with a solution of an amine in methanol with warming. 
A related imidazopyridine class of compounds may be prepared from intermediates shown in Scheme 40. 5-Hydroxypyridine 157 may be converted to the corresponding aniline 166 by heating in ammonium hydroxide saturated with sulfur dioxide in a pressure vessel (Newman and Galt, J. Org. Chem. 1960, 25, 214). After removal of the pivaloyl group of 166 with hydrochloric acid, the resulting diaminopyridine 167 may be condensed with methyl oxalyl chloride to give the imidazopyridine 168. The ester functionality may then be converted to amide 169 by treatment with ammonia in methanol, as described previously. 
Scheme 41 is an illustration of the preparation of thienopyridazine-containing inhibitors. The protected thiophene acid 170 was deprotonated with strong base (e.g. n-butyllithium), and reacted with a formylating reagent. The resultant oxazoline aldehyde 171 was hydrolyzed and cyclized with hydrazine to provide the hydroxy thienopyridazine 172. The hydroxy group was converted to the chloride 173 by the action of phosphorous oxychloride and subsequent substitution by alkoxides produced the ethers 174. The amide group is introduced in a manner analogous to that described above for the thienopyridines, providing amide 176. 
The syntheses of water-soluble glycosyl amide derivatives of general formula 178 are shown in Scheme 42. Tributylphosphine-mediated coupling of thienopyridine carboxylic acids of general formula 21 or 28 with 2,3,4,6-tetra-O-acetyl-D-glucopyranosyl azide with assistance of PyBOP smoothly furnished the protected xcex2-glycosyl amides of general formula 177 No other isomers were detected in the reaction. Cleavage of the acetyl groups with methyl amine provided compounds of general formula 178. 
Scheme 43 outlines the preparation of 4-(4-aminophenoxy)thieno[2,3-c]pyridine-2-carboxamide using a modification of the route described in Scheme 7. A two step sequence was adopted for assembling the thienopyridine core in the synthesis of 182. Treatment of the dichloropyridine aldehyde with one equivalent of N-BOC-protected 4-hydroxyaniline afforded compound 179, which was cyclized to give ester 180. Transformation to the amide 181 followed the previously described procedure, and the Boc-group was removed by treatment with trifluoroacetic acid. It should be noted that aniline 182 also serves as starting material for Sandmeyer reactions via the diazonium salt, in which the amino group may be converted to a variety of functional groups, including halo, hydroxy, cyano, among other standard Sandmeyer products. 
Scheme 44 exemplifies a general method for the preparation of 4-substituted aminophenoxythieno[2,3-c]pyridines using methodology described by Buchwald, et al. (Wolfe, John; Buchwald, Stephen L. J. Org. Chem. 1997, 62, 6066). Iodide 183, prepared by the previously described methods, was coupled with disubstituted amines (such as morpholine in the above example) in the presence of bis(dibenzylideneacetone)dipalladium and BINAP to provide the substituted aniline 184. 
Scheme 45 describes the preparation of 4-(4-hydroxymethylphenyl)thieno[2,3-c]pyridine 188, utilizing a modification of the route shown in Scheme 7. Starting with mono-tritylated 4-hydroxybenzyl alcohol, condensation with dichloroaldehyde 18, followed by cyclization with methyl thioglycolate, provided protected benzyl alcohol 188. Standard transformations provided alcohol 188. 
Scheme 46 describes the preparation of a protected benzyl alcohol 190, starting from mono-tetrahydropyran-protected hydroxybenzyl alcohol 189. Standard acid-catalyzed hydrolysis of the THP group can also yield the benzyl alcohol analog 188. 
As shown in Scheme 47, benzyl alcohol 188 may be further derivatized to esters, using standard coupling procedures, for example by carbodiimide conditions shown above, or by use of acid chloride. In addition, the alcohol may be converted to carbamates (R=NH2, mono or disubstituted amino) by treatment with isocyanates or carbamoyl chlorides. 
Glycosides of benzyl alcohol 187 may be produced using the procedure outlined in Scheme 48. Treatment of the alcohol 187 and tri-O-acetyl-D-glucal with stoichiometric scandium triflate afforded stereo-specifically protected glycoside 192, which was deprotected with methyl amine to give the free glycoside 193. 
Stille coupling of iodophenyl derivative 194 (or the corresponding bromophenyl analogs) with tributylethoxyvinyltin allows for the introduction of an acetyl group onto the 4-position of the phenyl ether as shown in Scheme 49. The intermediate vinyl ether is hydrolyzed during the work up conditions, thus providing acetophenone derivative 195. Addition of methylmagnesium bromide to ketone 195 at xe2x88x9250xc2x0 C. did not give the expected addition product, but rather aldol adduct 196 was isolated in 40% yield. The palladium catalyzed carbonylation of bromophenoxy methyl ester 197 in aqueous media afforded the acid 198 in modest yield. PyBOP- or EDC-mediated coupling with amines (illustrated above with morpholine), followed by amination of the 2-methyl ester, provided the diamides 199. 
In Scheme 50 the preparation of cinnamide ethers is described. Heck reaction of the bromophenoxy methyl ester 197 with t-butyl acrylate using tritolylphosphine as ligand furnished cinnamate 200 in good yield. Hydrolysis of the t-butyl ester with trifluoroacetic acid, followed by PyBOP or EDC-mediated coupling with an amine, and then amination of the methyl ester, provided diamide 201. 
Scheme 51 exemplifies the preparation of 4-heterocyclephenoxythienopyridines. Treatment of para-cyanophenyl derivative 202 with hydroxyamine in a mixture of DMF and ethanol smoothly gave hydroxyimidamide 203, which was heated with trifluoroacetic anhydride in pyridine to provide the oxadiazole 204. Cyano derivative 202 was transformed into imidazoline 205 under the conditions described above. Incorporation of other heterocycles was accomplished using known Stille, Suzuki, or Heck conditions as exemplified by the Stille coupling of iodo compound 194 and tributylstannylthiophene to provide compound 205A. The aryl coupling reactions described above may be applied to compounds with a variety of substituents at C-2 of the thienopyridine, in addition to the methyl amides exemplified in Scheme 51. 
Cyclopropylcarbinyl alcohol derivatives of the 4-phenyl ethers may be prepared according to the procedure described in Schemes 52 and 53. Commercially available phenylcyclopropane carboxylic acid is converted to the corresponding alcohol 206 by LAH reduction, then demethylation and selective protection of the hydroxymethyl group affords phenol 207. Using the procedure of Scheme 7, phenol 207 was condensed with dichloroaldehyde 18 and then methyl thioglycolate, to produce thienopyridine 208. Standard transformations led to the desired compounds 209 and 210. 
As shown in Scheme 53, alcohol 206 was alkylated to produce the polyether phenol 211 which was converted into cyclopropylcarbinyl polyether 212 using similar procedures described in Scheme 52. Such alkylation chemistry may be broadly applied by replacement of the diether tosylate shown with other alkyl halides or sulfonate esters. 
In Scheme 54, difluoroacetic acid derivative 213 was synthesized by a copper mediated coupling between iodide 194 and ethyl iododifluoroacetate in the presence of phenol, which was found to remarkably inhibit side reactions. Reduction of the ester 213 gave difluoroethyl alcohol 214. Alkylation of alcohol 214 with ethoxyethyl tosylate in the presence of sodium hydride and 15-crown-5 afforded polyether 215. 
An alternative synthesis of 4-alkoxythieno[2,3-c]pyridines through a phenolic alkylation strategy is outlined in Scheme 55. Mitsunobu alkylation of 5-chloro-3-hydroxypyridine provided benzyl ether 216, which was deprotonated with alkyllithium base and the resulting anion was treated with methyl formate to produce the pyridine carboxaldehyde 217. Construction of the thienopyridine core is accomplished by condensation with methyl thioglycolate under previously described conditions, leading to ester 218. This method may be applied to other alkyl ethers analogous to 216 to provide a variety of 4-alkoxy derivatives related to 218. Esters 218 were then converted to other active derivatives such as amides using previously described procedures. Benzyl ether 218 was hydrogenolyzed to phenol 219, which was converted to the corresponding amide 220 by standard procedures. Phenol 219 also serves as a partner in Mitsunobu reactions with a variety of primary or secondary alcohols, to provide alkyl ethers of general formula 221 (Huang, F., et al. J. Med. Chem. 1998, 41, 4216-4223). Esters of general formula 221 were converted to amides of general formula 222 by treatment under the standard conditions of reflux with methanolic amine solutions. 
Thienopyridine analogs bearing a 4-carbonyl group may be prepared by the procedures described in Scheme 56. Dichloropyridine aldehyde 18 was treated with methyl thioglycolate under previously described conditions to produce the 4-chlorothienopyridine ester 223. Ester exchange was accomplished by base catalyzed hydrolysis to acid 224, and tert-butyl esterification to 225 was accomplished with O-t-butyl trichloroacetimidate under Lewis acid catalysis. Palladium-catalyzed carbethoxylation proceeded under previously described conditions to give diester 226. Reduction/oxidation reactions led to the aldehyde 227, which was then condensed with arylmagnesium halide reagents (exemplified above with 4-chlorophenyl magnesium chloride) to produce alcohol 228. The ester 228 may be transformed to various 2-substituted thienopyridine analogs directly, or oxidized to the corresponding 4-keto derivative 230. Standard transformation of ester 230 to amide 231 completes the synthesis. It should be noted that ester 226 may be selectively converted to amide derivatives by initial alkaline hydroysis of the ethyl ester, coupling to an amine, then acidic hydrolysis of the tert-butyl ester, and finally coupling to another amine to produce 308. 
A variety of 2-substituted thieno[2,3-c]pyridines are accessible from 2-esters of general formula 20 and 25. Scheme 57 exemplifies products which may be obtained from hydroxymethyl derivatives of general formula 232. Calcium borohydride reduction of esters of general formula 20 or 25 provided alcohols of general formula 232. Swern oxidation cleanly provided aldehydes of general formula 233. This versatile intermediate may be converted to olefins by standard Wittig conditions, as exemplified by the preparation of 2-vinylthienopyridines of general formula 234 (Hibino, S. J. Org. Chem. 1984, 49, 5006-5008). Additional modification to dihydroxyethyl compound 235 was accomplished through the use of catalytic osmium tetroxide with 4-methylmorpholine N-oxide as stoichiometric oxidant. 
Scheme 58 illustrates the conversion of aldehyde 233 to the acrylate 236, which was accomplished by Homer-Emmons condensation with trimethyl phosphonoacetate (Jung, M. E. and Kiankarami, M. J. Org. Chem. 1998, 63, 2968-2974). The described methods may be extended to analogs bearing a wide variety of C-4 substituents, including aryloxy, alkoxy, arylamino, aryl, alkyl. The derived ester 236 was then subjected to hydrolysis to provide acid 237. Carboxylic acid 237 was subjected to standard coupling conditions to produce amide 238. The derived acrylates of general formula 239 may be oxidized to the corresponding diols of general formula 240 with catalytic osmium tetroxide in the presence of 4-methylmorpholine-N-oxide. 
Scheme 59 illustrates the use of aldehyde 233, with LAXA=aryloxy, as starting material for the preparation of oxime derivatives of general formula 241. The strategy outlined is generally applicable to analogs with a variety of LAXA substituents. Aldehydes of general formula 233 were also reacted with organomagnesium (or organolithium) reagents to produce secondary alcohols which were oxidized to the corresponding ketones of general formula 242. Oxidation is preferably accomplished by standard Swern conditions (DMSO and oxalyl chloride in CH2Cl2 solution at low temperature, followed by treatment with tertiary amines such as ethyldulsopropyl amine), but other conditions (tetra-n-propyl perruthenate, manganese dioxide) may be employed. The ketones were then converted to oximes of general formula 243 by previously described methods. 
The preparation of 2-heterocyclic thienopyridines of general formula 249 is illustrated in Scheme 60. Primary amides of general formula 26 were treated with excess trifluoroacetic anhydride in pyridine to smoothly produce nitriles of general formula 244, which serves as a convenient intermediate for the preparation of amidine and azole derivatives. Thus, nitriles of general formula 244 were converted to the amidoximes of general formula 245 by treatment with hydroxylamine hydrochloride and triethylamine. Reaction of amidoximes of general formula 245 with acetyl chloride, trifluoroacetic anhydride, triethylorthoformate or trichloroacetyl chloride in pyridine produced the oxadiazoles of general formula 246 with variations in X dictated by the choice of acylating/dehydrating reagent. The trichloromethyl oxadiazoles of general formula 246 (Xxe2x95x90CCl3) were converted to the 5-amino-1,2,4-oxadiazoles of general formula 247 by heating with ammonia in a sealed tube. Nitriles of general formula 244 were also converted to cyanoamidines of general formula 248 when subjected to excess cyanamide in THF with DBU as the base. The 3-amino-1,2,4-oxadiazoles of general formula 249 were then generated by treatment of cyanoamidines of general formula 248 with hydroxylamine hydrochloride and triethyamine in methanol. 
Scheme 61 depicts the preparation of 2-arylcarbonylthienopyridines. Thienopyridines of general formula 44 were deprotonated with alkyllithium base and condensed with nitrobenzaldehdyes to produce the benzyl alcohols of general formula 250. Tin(II)-induced reduction of the nitrophenyls to the anilines of general formula 251 were followed by selective alcohol oxidation with pyridinium chlorochromate. The nitro benzyl alcohols of general formula 250 were also converted to the corresponding ketones of general formula 253 under Swern conditions (for example, oxalyl chloride/DMSO/CH2Cl2 at low temperature, followed by treatment with amine bases). 
Scheme 62 depicts the preparation of 2-carbamatethienopyridines and 2-ureathienopyridines. Alcohols of general formula 232 were converted to the amines of general formula 254 by Mitsunobu reaction with phthalimide, followed by deprotection with hydrazine. The amines of general formula 254 were converted to the corresponding ureas of general formula 255 by reaction with potassium isocyanate under acidic conditions. Similarly, the alcohols of general formula 232 were converted to the corresponding carbamates of general formula 256. This chemistry is generally applicable to the use of substituted isocyanates or carbamoyl chlorides, leading to mono or disubstituted carbamates or ureas. 
Scheme 63 illustrates the preparation of 2-thioureathienopyridines, starting from 2-aminothienpyridines of general formula 54. Reaction of 54 with substituted isothiocyanates in pyridine at reflux provided the thioureas of general formula 257. 
Scheme 64 exemplifies the synthesis of sulfonamides at the 2-position of the thienopyridines. An improved procedure for decarboxylation of thienopyridine-2-carboxylic acids is shown, wherein acids of general formula 21 were heated in diphenylether at 210xc2x0 C. to provide thienopyridines of general formula 44 in high yield. Compounds 44 were deprotonated with strong base, then treated with sulfir dioxide to produce intermediate sulfinic acids. Addition of N-chlorosuccinimide produced sulfonyl chlorides of general formula 258, from which a variety of sulfonamides of general formula 259 were prepared by reaction with ammonia, primary or secondary amines in the presence of diisopropylethylamine in protic solvents such as methanol (Prugh, J. D., et al. J. Med. Chem. 1991, 34, 1805-1818; Davidsen, S. K., et al. J. Med. Chem. 1998, 41, 74-95). 
Scheme 65 provides the outline of the synthesis of additional 2-arylthienopyridines with amino or hydroxy groups on the aryl ring. Using the method of Scheme 24, Suzuki coupling of boronic acids of general formula 79 with nitro-substituted aryl iodides produced biaryls of general formula 260. Biaryls of general formula 260 were reduced to the aminophenyl derivatives of general formula 261 with tin(II) chloride. Methyl ethers of general formula 262 were prepared from boronic acids 79 by coupling with methoxy iodobenzenes, and were converted to the hydroxy derivatives of general formula 263 through the use of boron tribromide to demethylate the methyl ethers. 
Schemes 66-71 illustrate syntheses for additional 5-membered heterocycles at the 2-position of the thienopyridines. Scheme 66 outlines a method for producing 1,3,4-oxadiazoles. Hydrazides of general formula 264 were prepared by treating esters of general formula 20 or 25 with hydrazine in methylene chloride. The hydrazides were converted to 5-amino-1,3,4-oxadiazoles of general formula 265 by reaction with cyanogen bromide. Hydrazides of general formula 264 may be converted to 5-unsubstituted or 5-alkyl-substituted-1,3,4-oxadiazoles of general formula 266 by condensation with orthoesters under reflux conditions. 
Scheme 67 indicates a method of preparing 1,3,4-triazoles from methyl esters of general formula 20 or 25. Condensation with aminoguanidine under basic conditions (for example sodium methoxide in methanol) produced the 2-amino-1,3,4-triazoles of general formula 267. Nonspecific methylation was performed on 1,3,4 triazoles of general formula 267 using sodium hydride and methyl iodide, which provided mono-methyl triazoles of general formula 268, dimethyl triazoles of general formula 269, and trimethyl triazoles of general formula 270, which were chromatographically separable. 
Scheme 68 indicates a method for the preparation of 1,3,4-thiadiazoles of general formula 272. The acid chlorides derived from acids of general formula 21 or 28 were reacted with thiosemicarbazide or substituted thiosemicarbazides to give intermediate acylated thiosemicarbazides of general formula 271, which were cyclized under acid catalysis (for example methanesulfonic acid in refluxing toluene) to provide thiadiazoles of general formula 272. 
Scheme 69 provides a method for the preparation of 1,3,4-oxadiazol-2-thiones and the derived alkylthio-substituted oxadiazoles of general formula 274. Hydrazides of general formula 264 were treated with carbon disulfide in potassium hydroxide in aqueous ethanol solution to give the cyclic thiocarbamates of general formula 273. The thiocarbonyl group was alkylated in low yield with alkyl halides to give the alkylthio 1,3,4-oxadiazoles of general formula 274. 
Scheme 70 shows the preparation of tetrazoles at the 2-position of thienopyridines. 2-Cyano derivatives of general formula 244 were converted to tetrazoles of general formula 275 using trimethylsilyl azide in the presence of catalytic dibutyltin oxide. The tetrazoles were converted to the N-methyl derivatives of general formula 276 by use of a solution of diazomethane in methanol. 
Scheme 71 illustrates the syntheses of 2-oxazole and 2-imidazole thienopyridines. Chloroethyl amides of general formula 277 were prepared by chlorination of the corresponding hydroxyethyl amides and then cyclized to oxazolines of general formula 278 under basic catalysis (for example, diazabicycloundecane in dichloromethane). The oxazolines of general formula 278 may be converted to the oxazoles of general formula 278 by dehydrogenation according to the procedure of Meyers (Meyers, A. I., et al. J. Amer. Chem. Soc. 1975, 97, 7383). Aminoethyl amides of general formula 280 were cyclized to the imidazolines of general formula 281 by treatment with calcium oxide at high temperature in diphenyl ether. Imidazolines of general formula 281 may be converted to imidazoles of general formula 282 by literature methods (Hughey, J. L., et al. Synthesis [SYNTBF] 1980, (6), 489). 
In Scheme 72, an improved preparation of 3-alkyl-substituted thienopyridines of general formula 115 is disclosed. Aldehyde 18 was condensed with preformed potassium phenoxides to produce a mixture of mono- and disubstituted aryloxyaldehydes. This mixture was then reacted with the desired Grignard reagent, followed by a Swern oxidation of the resultant mixture of secondary alcohols to give the desired aryloxy ketone compounds. The mixture of aryloxy ketones were further reacted with methyl thioglycolate in the presence of cesium carbonate to provide the 2,3,4-trisubstituted thieno[2,3-c]pyridine esters of general formula 114. These esters were converted to the corresponding acids by hydrolysis with lithium hydroxide, and then the acids were coupled with various amines, for example by carboduimides, to give the desired amides of general formula 115. 
Scheme 73 provides a synthesis for 3-carboxythienopyridines. Using methodology analogous to that described for the preparation of 20 or 25, 3,5-dichloropyridine was treated with strong base such as lithium diisopropylamide in anhydrous ethereal solvent at low temperature, followed by the addition of t-butyl chlorooxoacetate to provide the 4-tert-butyl-2-ketoester of 3,5-dichloropyridine 283. The ester 283 was then reacted with 1.25 equivalents of preformed potassium phenoxides at ambient temperature, to give the monoaryloxy derivatives as the main product. Without purification, the monoaryloxy esters were treated with methyl thioglycolate and base such as potassium t-butoxide or cesium carbonate to provide the desired thienopyridine diesters of general formula 284. The diesters of general formula 284 were then treated with methanolic amines to give the corresponding 3-tert-butyl ester amides of general formula 285. The tert-butyl ester amides of general formula 285 were converted to the corresponding acid amides of general formula 287 by solvolysis with trifluoroacetic acid. Diesters of general formula 284 may also be converted to the acids of general formula 286 by a similar solvolysis reaction. 
Scheme 74 describs the use of 4-bromothienopyridine 32 to prepare 4-amino substituted thienopyridine derivatives. Ester 32 was converted to amides of general formula 288 by standard procedures, and then coupled to a variety of amines using palladium(0) catalysis, as described by Buchwald (J. Org. Chem. 1997, 62, 6066-6068), producing 4-amino derivatives of general formula 289. 
Scheme 75 outlines the preparation and reactions of 7-chloro and 7-bromothienopyridine derivatives. The analogs are useful for preparing active derivatives as well as serving as synthetic intermediates for a variety of 7-substituted thienopyridines. Esters of general formula 25 were oxidized to the pyridine-N-oxides of general formula 290 with meta-chloroperbenzoic acid. The N-oxides were rearranged to the 7-halo derivatives of general formula 291 by warming in phosphorous oxychloride or phosphorous oxybromide. The resultant 7-halides could be converted to the amide derivatives of general formula 292 by standard methods without reaction of the 7-chloro or 7-bromo moieties. However, under more forcing conditions, the chloro or bromo groups could be substituted with amines or alcohols to provide 7-amino derivatives of general formula 293 and 7-alkoxy derivatives of general formula 294 respectively. Esters of general formula 294 were converted to amides of general formula 295 using standard methods. 7-Hydroxy analogs of general formula 296 were prepared from 291 derivatives using acetic anhydride followed by hydrolysis with water. In addition, the 7-halo derivatives 291, in particular the 7-bromo derivatives, were effective educts in Suzuki reactions with aryl boronic acids, similar to those described in Scheme 19 and 65. 
Scheme 76 describes the preparation of furopyridine analogs such as 299 (Example 327). By a procedure analogous to that of the preparation of 20 or 25, dichloropyridinecarboxaldehyde 18 was reacted sequentially with a potassium phenoxide, then with ethyl glycolate, followed by cyclization under basic conditions, affording furopyridine ester 298 in low yield. Standard hydrolysis and coupling conditions afforded the amide 299. The amide was converted to the thioamide 300 by treatment with Lawesson""s reagent in hot toluene. 
Scheme 77 illustrates the preparation N-alkyl 5-amino-1,3,4,-oxadiazoles. The treatment of 265 in refluxing trimethylorthoformate followed by reduction of the eneamine intermediate with sodium borohydride in refluxing ethanol provides the N-alkylated 5-amino-1,3,4,-oxadiazoles of general formula 301. 
Scheme 78 exemplifies the synthesis of substituted vinyl moieties at the 4-position of thienopyridines. Treatment of aldehyde 227 with the appropriate diethylphosphonate in the presence of potassium bis(trimethylsilyl)amide provided 302. Compound 302 was then treated with sulfuric acid in methanol to yield the methyl ester 303, followed by standard amide formation with ammonia and methanol to produce 4-vinylsubstituted thienopyridines of general formula 304. Installation of a substituted vinyl can also be accomplished by using Wittig phosphorane chemistry. 
Scheme 79 demonstrates the preparation of 4-substituted alkyl thienopyridines. Alcohol 228 was subjected to palladium on carbon in acetic acid to generate the methylene derivative 305. Treatment of 305 with sulfuric acid in methanol yields 306. Formation of the amide is accomplished by treatment of 306 with ammonia in methanol to yield 307 
Scheme 80 illustrates the preparation of thiazole derivatives at the 2-position of thienopyridines. Thioamides of general formula 309 were alkylated and cyclized with ethyl bromopyruvate, providing thiazole esters of general formula 310. Standard amide formation led to amides of general formula 311. Other amines may be used to produce a variety of substituted amides. In addition, esters of general formula 310 may be converted to carbamates of general formula 312 through Curtius rearrangement of the intermediate acid. The tert-butyl carbamates of general formula 312 were converted to the primary amines of general formula 313 by the action of trifluoroacetic acid. 
Scheme 81 outlines an alternative method for preparing 3-substituted thienopyridines, wherein Ar=unsubstituted or substituted aryl, or heterocycle, and R=alkyl, alkoxy, substituted alkyl, aryl, arylalkyl. Aldehyde 18 was reacted with the appropriate organomagnesium halide, to give an intermediate secondary alcohol, which was oxidized to the corresponding ketone 314. The method of oxidation was the Swern procedure, although other standard oxidations of this type may be employed (e.g PCC, TPAP). The procedure then follows that previously described for the 3-unsubstituted analogs, leading to ester 315. Ester 315 then served as starting material for the preparation of amides, or other heterocyclic derivatives at the 2-position of the thienopyridines. 
Scheme 82 describes a method for producing cyclic derivatives between the 2- and 3-positions of thienopyridines. 3-Methyl derivative 115 was treated with N-bromosuccinimide (or alternatively N-chlorosuccinimide) in carbon tetrachloride to give bromomethyl (or chloromethyl) compound 316 (X=Br, Cl). Compound 316 can then be reacted with a primary amine, through alkylation and acylation, leading to the tricyclic lactam 317. Compound 316 may also be treated with sodium alkoxides or aryloxides R2 =alkyl, aryl, or heterocycle) leading to the 3-position extended alkoxymethyl derivatives 318. These esters in turn can be reacted with substituted amines to yield the corresponding amides 319.
The compounds and processes of the present invention will be better understood in connection with the following examples which are intended as an illustration of and not a limitation upon the scope of the invention.